Dosing regimens for fast onset of antidepressant effect

ABSTRACT

A dose regimes comprising the simultaneous administration of two pharmaceutical compositions, wherein the first pharmaceutical composition is a composition comprising vortioxetine or a pharmaceutically acceptable salt thereof for once daily oral administration, and the second pharmaceutical composition is a composition comprising vortioxetine or a pharmaceutically acceptable salt thereof which together with said first composition quickly achieves a steady-state plasma level of vortioxetine in said patient which steady-state plasma level is the same as the steady-state vortioxetine plasma level achieved by the administration to said patient of said first composition alone.

CROSS REFERENCE TO PRIOR APPLICATION

This application claims priority to U.S. Provisional Application Ser.No. 62/357,722, filed Jul. 1, 2016, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to a treatment regimen for vortioxetine

BACKGROUND

The compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine wasfirst disclosed in the International patent application published as WO03/029232. Later, International patent applications including WO2007/144005, WO 2011/023194 and WO 2010/121621 have disclosedcrystalline forms, manufacturing processes, formulations, and inparticular liquid formulations of said compound. World HealthOrganization (WHO) has recommended the INN name “vortioxetine” for1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine. Vortioxetineobtained first regulatory approval in September 2013 in the UnitedStates of America for the treatment of major depressive disorder and hassince then obtained approvals for similar indications throughout theWorld.

Vortioxetine has multimodal activity, and it has been shown to be anantagonist on the 5-HT3, 5-HT7 and 5-HT1D receptors, an agonist at the5-HT1A receptor and a partial agonist at the 5-HT1B receptor, and aninhibitor of the serotonin transporter (SERT). 5-HT abbreviates5-hydroxy tryptamine, i.e. serotonin. Moreover, vortioxetine hasdemonstrated to increase the levels of important neurotransmittersincluding serotonin, noradrenaline, dopamine, acetylcholine andhistamine in specific areas of the brain [J. Med. Chem., 54, 3206-3221,2011; Pharmacol. & Therap., 145, 43-57, 2015].

A significant drawback for treatment of depression using oral serotoninreuptake inhibitors is the lag-period between onset of treatment andonset of action which can be many weeks.

Several advantages have been suggested for intravenous (IV)administration of antidepressants compared to oral administration. IVadministration avoids first-pass metabolism, and compliance is less of aproblem compared to oral administration. In addition, it has beensuggested that the IV setting itself may have a favourable impact on thetreatment outcome. Finally, and with particular relevance in the presentcontext, some reports in prior art suggest a faster onset of action forIV administration although only a few studies have applied thedouble-blind/double-dummy study design needed to properly compare onsetof action between oral and IV administration of antidepressants.

Häberli in Pharma-Kritik, 10, 41-44, 1988 reviews studies comparingclomipramine (tricyclic antidepressant (TCA) with mainly serotoninreuptake inhibitory activity) and maprotilin (tetracyclic antidepressantwith mainly noradrenaline reuptake inhibitory activity) in oral and IVadministration settings. The conclusion is that antidepressant IVtherapy has failed to deliver on the promise of faster onset of action.

Oral and IV administration of amitryptilin (TCA with serotonin and alsonoradrenaline reuptake inhibitory activity) have been compared in adouble-blind/double-dummy study [J Clin Psychpharm 20, 417-422, 2000].No difference in onset of action between the two treatments could bedetected.

Oral and IV administration of citalopram (selective serotonin reuptakeinhibitor (SSRI)) have been compared in several studies.Neuropsychiatrie 6, 65-71, 1992 reports on an open-label study wheredepressed patients received repeated oral (N=475) or IV citalopram(N=284) for 10-14 days followed by 4-6 weeks of oral treatment. Anearlier onset of action in the IV treated group was observed although italso has to be noticed that the mean dose during the first 10-14 daysfor the IV treated patients was twice that of the dose for the orallytreated patients. More than 50% of the participating doctors withpatients on initial IV treatment indicated that an expectation of fasteronset was the main reason for administering IV treatment to theirpatients.

{hacek over (C)}esko-Slovenská Psychiatrie, 6, 331-339, 1993 reports ona study where 101 depressed patients were enrolled in an open-labelstudy to receive either 28 days oral citalopram or 14 days IV citalopramfollowed by 14 days oral citalopram. A significantly faster onset ofaction was observed in the IV treated group.

J Affec Dis, 49, 203-210, 1998 reports on a double-blind, double-dummystudy comparing oral and IV administration of citalopram. 60 depressedpatients were treated with either repeated citalopram tablets andplacebo IV or repeated citalopram IV and placebo tablets for 10 daysfollowed by oral citalopram for additional 32 days. No statisticaldifference in onset of action could be detected between the two groupsfor any efficacy parameter although a tendency toward a quicker onset ofaction was seen when measured as percentage of patients with more than50% reduction of the score on the Hamilton Depression Scale compared tobaseline.

J Affect Dis 58, 201-209, 2000 reports on a further double-blind,double-dummy study comparing oral and IV administration of citalopram.Depressed patients were randomised to repeated citalopram tablets andplacebo IV (N=119) or repeated citalopram IV and placebo tablets (N=135)for 8 days followed by 34 days of oral citalopram treatment. Nodifference in the Montgomery-Åsberg Depression Rating Scale (MADRS) atday 8 was found, which was the primary efficacy end-point. However,improvements on the Global Clinical Impression scale at day 8 wereobserved for more patients in the IV arm than in the oral arm.

In conclusion, past well-controlled studies have generally failed toshow a faster onset of action for antidepressants, and in particular forantidepressant with serotonin reuptake inhibitory effect, administeredvia the IV route compared to oral administration.

Basic & Clin Pharmacol & Tox, 111, 198-205, 2012 discloses a series ofstudies to define the clinical pharmacokinetics of vortioxetine. One ofthe studies was a single-dose, open-label, 2-way crossover study wherehealthy volunteers received oral and IV vortioxetine with a wash-outperiod of at least 18 days between the two administrations.

One aim of the present invention is to provide a treatment regime forvortioxetine which achieves a faster onset of action compared to orallyadministered vortioxetine.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that vortioxetine,contrary to what is found for SSRI's, gives rise to a large increase inserotonin concentrations in parts of the brain relevant for mood uponacute administration. Such increase in serotonin concentration isindicative of a fast or immediate onset of antidepressant action.Accordingly, in one embodiment, the invention provides a method for thetreatment of depression, said method comprising the simultaneousadministration of two pharmaceutical compositions to a patient in needthereof, wherein the first pharmaceutical composition is a compositioncomprising vortioxetine or a pharmaceutically acceptable salt thereoffor once daily oral administration, and the second pharmaceuticalcomposition is a composition comprising vortioxetine or apharmaceutically acceptable salt thereof which together with said firstcomposition achieves a steady-state plasma level of vortioxetine in saidpatient within 36 hours from said simultaneous administration whichsteady-state plasma level is essentially the same as the steady-statevortioxetine plasma level achieved by the administration to said patientof said first composition alone.

In one embodiment, the invention relates to an oral pharmaceuticalcomposition comprising vortioxetine or a pharmaceutically acceptablesalt thereof for once daily oral administration for use in the treatmentof depression wherein said oral pharmaceutical composition issimultaneously administered to a patient in need thereof with apharmaceutical composition comprising vortioxetine or a pharmaceuticallyacceptable salt thereof and wherein said simultaneous administrationachieves a steady-state vortioxetine plasma level within 36 hours fromsaid simultaneous administration in said patient which steady-statevortioxetine plasma level is essentially the same as the steady-statevortioxetine plasma level achieved by the administration to said patientof said oral pharmaceutical composition alone.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising vortioxetine or a pharmaceutically acceptable salt thereoffor use in the treatment of depression wherein said pharmaceuticalcomposition is simultaneously administered to a patient in need thereofwith an oral pharmaceutical composition comprising vortioxetine or apharmaceutically acceptable salt thereof for once daily administrationwherein said simultaneous administration achieves a steady-statevortioxetine plasma level within 36 hours from said simultaneousadministration in said patient which steady-state vortioxetine plasmalevel is essentially the same as the steady-state vortioxetine plasmalevel achieved by the administration to said patient of said oralpharmaceutical composition alone.

In one embodiment, the invention relates to two pharmaceuticalcompositions for use in a method for the treatment of depression whichcompositions are simultaneously administered to a patient in needthereof, wherein the first pharmaceutical composition is a compositioncomprising vortioxetine or a pharmaceutically acceptable salt thereoffor once daily oral administration and the second pharmaceuticalcomposition is a composition comprising vortioxetine or apharmaceutically acceptable salt thereof which together with said firstcomposition achieves a steady-state plasma level of vortioxetine in saidpatient within 36 hours from said simultaneous administration whichsteady-state vortioxetine plasma level is essentially the same as thesteady-state vortioxetine plasma level achieved by the administration tosaid patient of said first composition alone.

In one embodiment, the invention relates to the use of vortioxetine or apharmaceutically acceptable salt thereof in the manufacture of a firstpharmaceutical composition for once daily oral administration for thetreatment of depression, wherein said first pharmaceutical compositionis administered to a patient simultaneous with a second pharmaceuticalcomposition comprising vortioxetine or a pharmaceutically acceptablesalt thereof and wherein said simultaneous administration achieves asteady-state vortioxetine plasma level within 36 hours from saidsimultaneous administration in said patient which steady-statevortioxetine plasma level is essentially the same as the steady-statevortioxetine plasma level achieved by the administration to said patientof said first composition alone.

In one embodiment, the invention relates to the use of vortioxetine or apharmaceutically acceptable salt thereof in the manufacture of apharmaceutical composition for the treatment of depression, wherein saidpharmaceutical composition is administered to a patient simultaneouswith a once daily oral pharmaceutical composition comprisingvortioxetine or a pharmaceutically acceptable salt thereof and whereinsaid simultaneous administration achieves a steady-state vortioxetineplasma level in said patient within 36 hours from said simultaneousadministration which steady-state vortioxetine plasma level isessentially the same as the steady-state vortioxetine level achieved byadministration of said oral pharmaceutical composition to said patientalone.

BRIEF DESCRIPTION OF DRAWING

FIG. 1: The study design used for the PET studies in Example 1. {circlearound (1)} Administration of [¹¹C]AZ10419369 or [¹¹C]MADAM; {circlearound (2)} administration of vortioxetine 0.3 mg/kg IV, vortioxetine 1mg/kg IV, or citalopram 0.3 mg/kg IV; {circle around (3)} Administrationof [¹¹C]AZ10419369 or [¹¹C]MADAM.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to vortioxetine or a pharmaceuticallyacceptable salt thereof. Vortioxetine is commercially available or canbe synthesised as disclosed in e.g. WO 03/029232, WO 2007/144005 or WO2014/128207. The molecular structure of vortioxetine is depicted below.

In the present context “pharmaceutically acceptable salt” is intended toindicate a salt formed in the reaction between vortioxetine and anon-toxic acid. Examples of such acid include hydrochloride acid,hydrobromide acid, phosphoric acid, nitrous acid, sulphuric acid,benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid,succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid,maleic acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylicacid and sulfonic acids, such as ethanesulfonic acid, toluenesulfonicacid and benzenesulfonic acid. Specific mention is made of the HBr andthe DL-lactic acid salts. Additional examples of useful acids to formpharmaceutically acceptable salts can be found e.g. in Stahl and Wermuth(Eds) “Handbook of Pharmaceutical salts. Properties, selection, anduse”, Wiley-VCH, 2008.

Any indication of an amount or concentration of vortioxetine or apharmaceutically acceptable salt thereof is intended to indicate suchamount or concentration as the free base, unless otherwise specificallyindicated. The molecular weight of vortioxetine HBr is 379.4 g/mol andthat of vortioxetine is 298.5 g/mol. Therefore, a composition comprisingvortioxetine HBr indicated to comprise 20 mg vortioxetine actuallycomprises 25.4 mg vortioxetine HBr.

Depression is a mental state characterised by, e.g., depressed mood anda feeling of sadness, emptiness, helplessness or worthlessness. As apsychiatric syndrome depression includes depressive disorders, e.g. asdefined in DSM-V. Depressive disorders include disruptive mooddysregulation disorder, major depressive disorder, persistent depressivedisorder and premenstrual dysphoric disorder. In one embodiment,“depression” is intended to indicate major depressive disorder.

Treatment of depression using serotonin reuptake inhibitors is oftencharacterised by a delay between the treatment start and the onset oftherapeutic action. This delay is typically measured in weeks, and thedelay is critical for several reasons including the fact that remissionis more likely to be achieved in patients with a fast treatmentresponse. Obviously, a patient would normally also wish for a fastresolution of symptoms related to any disease, including depression. Itmay also be noted that patients may only experience the adverse eventsassociated with the antidepressant treatment in that period without thebenefit of a therapeutic effect. Therefore, there is a risk thatpatients may stop taking the antidepressant with the consequent reducedlikelihood of a successful treatment. Moreover, the lag-time betweenonset of treatment and onset of action has been associated with anincreased risk of suicide [Eur Neuropsychoparm 13, 57-66, 2003].

The latency of onset of clinical effect from antidepressant treatment,including treatment with serotonin reuptake inhibitors, has beenrecognised as a major limitation since the advent of these drugs. Thatthis limitation still exists is evidenced by two review articlesspanning the last decade—see Pharmacol & Ther, 113, 134-153, 2007 andEur J Pharmacol, 753, 32-50, 2015.

Serotonin is a neurotransmitter passing nerve signals between nervecells (neurons) over the synaptic cleft. A presynaptic (orsignal-passing) neuron releases serotonin into the synaptic space inresponse to electrical activity in said cell. Here, serotonin interactswith receptors in the membrane of a post-synaptic (or signal-receiving)neuron and thereby passes the nerve signal from one cell to the other.To maintain this mechanism, serotonin is subsequently reabsorbed intothe neurons via the serotonin transporter which is a protein complexlocated in the cell membrane of the neuron. According to the monoaminetheory for depression, depression is associated with inadequate nervesignalling in parts of the brain, and the effect of serotonin transportinhibitors may be explained by a blocking of the serotonin transporter(i.e., the serotonin reuptake) thereby causing an increase of serotoninin the synaptic cleft and a normalization of nerve signalling.

The delay of onset of action has been explained by several factorsincluding activation of serotonin receptors, and in particular theserotonin receptor 1A (5-HT_(1A)). The increase in synaptic serotoninlevel as a consequence of the inhibition of serotonin reuptakestimulates 5-HT_(1A) receptors which are part of a feedback inhibitorysystem bringing about a lower release of serotonin from the pre-synapticneurons. Over time (several weks), the 5-HT_(1A) receptors aredesensitized, the feedback inhibitory system inactivated and theserotonin release normalised which together with the inhibition ofserotonin reuptake eventually causes an increase in serotonin in thesynapse [J Clin Psych 62 (suppl 15) 12-17, 2001].

In clinical practice, treatment with antidepressants is normallycontinued for a considerable amount of time after a successfulresolution of the symptoms of depression has been achieved in order tominimize the risk of relapse [The Maudsley Prescribing Guidelines,9^(th) Edition, Informa Healthcare, 2008].

It has been suggested that adding a 5-HT_(1A) receptor partial agonistor antagonists, such as pindolol, to an SSRI treatment could give riseto a blocking or faster desensitization of the 5-HT_(1A) receptors andtherefore a faster onset of action and/or an augmentation of theantidepressant effect. It has also been suggested that the combinationof a serotonin reuptake inhibitor with compounds acting on various otherserotonin receptors, such as 5-HT_(2A) and 5-HT_(2C) receptorantagonists provides a faster increase in serotonin in the synapticcleft implying a faster onset of action or increased effect [BiochemPharmacol, 95, 81-97, 2015]. However, clinical investigations ofpindolol as add-on to antidepressants have delivered mixed results withopen label studies often favouring the combination but with lack ofsupport to these findings from controlled studies [Br J Psych 173,203-208, 1998].

Recently approved antidepressants with a pharmacological profile whichcould hold a promise of a faster onset of action have not successfullyshown a shorter period of time between onset of treatment and onset ofaction. Vilazodone is a serotonin reuptake inhibitor and 5-HT_(1A)receptor partial agonist approved by FDA for the treatment of depressionin 2011. Despite early reports of faster onset of action, the pivotalstudies did not support such claim [J Clin Psych, 72, 1166-1173, 2011].More recently, FDA approved vortioxetine which, as discussed above, is amultimodal compound with a pharmacological profile which includesserotonin reuptake inhibition and 5-HT_(1A) receptor agonism. However,according to the FDA label for vortioxetine of July 2014 an effect ofvortioxetine is observed starting at week 2 and with the fullantidepressant effect of the drug not seen until week 4.

More recently, alternatives to augmented SSRI treatment have beensuggested as ways to achieve a faster onset of antidepressant effect.Wilner et al in Neurosci Biobehav Rev, 37, 2331-2371, 2013 suggest deepbrain stimulation (DBS) which is a neurosurgical treatment where anelectrode, which sends electrical impulses, is implanted in the brain asa way to achieve fast onset of effect. Similarly, electroconvulsivetherapy (ECT), intravenous administration of ketamine and REM-sleepdeprivation are suggested as fast onset antidepressant techniques.

As discussed above, and according to the monoamine theory, depression isa disorder caused by low serotonergic activity, and treatment with e.g.,serotonin reuptake inhibitors is intended to induce an increase inserotonin level in the brain which will normalize this activity andthereby treat the disease. A faster increase in the serotonin level inrelevant parts of the brain would be expected to be associated with afaster onset of treatment effect.

Positron emission tomography (PET) is an imaging technique which allowsthe measurement of the level of radio nucleotides (as part of the PETligand) introduced into the body. The recent advent of a PET ligandwhich specifically binds to the 5-HT_(1B) receptor, [¹¹C]AZ10419369, hasmade possible the use of PET scanners to non-invasively determinealterations in serotonin level in specific areas of the brain relevantfor mood [Int J Neuropsychpharm 16, 1577-1586, 2013]. The chemical namefor [¹¹C]AZ10419369 is5-methyl-8-(4-[¹¹C]methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylicacid (4-morpholin-4-yl-phenyl)-amide. In summary, the PET ligand bindsspecifically to the 5-HT_(1B) receptor and is displaced by theendogenous ligand, serotonin, if the level of serotonin increases. Thus,a decrease in the PET ligand-5-HT_(1B) receptor specific binding(measured as binding potential, BP_(ND)) upon administration of a drugis taken to indicate an increase in the serotonin level in thatparticular part of the brain. Conversely, an increase in BP_(ND) istaken to indicate a decrease in serotonin level.

The central serotonergic system in the brain originates in the raphenuclei (RN) which is divided into several subgroups with, in particular,the dorsal raphe nucleus (DRN) projecting into the cortical and striatalareas of the brain. Using PET scanning with [¹¹C]AZ10419369 as ligandchanges in relevant parts of the brain of monkeys upon acuteadministration of the SSRI escitalopram (2.0 mg/kg) have beendetermined. The parts in the brain investigated included thedorsolateral prefrontal cortex (DLPFC), the occipital cortex (OC), thecaudate nucleus (CN), the putamen (Put), the thalamus (Thal), the globuspallidus (GP) the midbrain (MB), the hippocampus and the cerebellum (CB)[Int J Neuropsychpharm 16, 1577-1586, 2013]. The table below shows thechanges in BP_(ND) in the various brain regions.

Region ΔBP_(ND) (% of baseline) p value DLPFC −12 ± 12   0.03 OC 12 ± 100.02 CN  −9 ± 14   0.1 Put −11 ± 14   0.1 Thal −13 ± 8    0.005 GP  −7 ±10   0.08 MB −11 ± 10   0.03 HC −12 ± 14   0.07 RN −25 ± 16   0.002

Similarly, the change in BP_(ND) upon acute administration ofescitalopram (20 mg per oral) in humans (healthy volunteers) wasdetermined with the result indicated in the table below. Additionalprojections in the brain investigated were the frontal cortex (FC) andthe temporal cortex (TC).

Region ΔBP_(ND) (% of baseline) p value FC 6 ± 7 0.05 OC 5 ± 5 0.01 TC 5± 6 0.04 CN  6 ± 10 0.1 Put 5 ± 8 0.08 Thal  6 ± 13 0.2 RN  −9 ± 13  0.08 Cortical regions 5 ± 5 0.01 Subcortical regions 6 ± 8 0.07 Allprojection areas 5 ± 5 0.01

Overall, the change in BP_(ND) in both human and monkey is relativelysmall in most projections of the brain and often not significant. Theresults from the monkey studies seem to suggest a small and not alwayssignificant decrease in BP_(ND), i.e. an increase in serotonin levelupon escitalopram administration. However, it has to be kept in mindthat the dose administered to the monkey gave a plasma level which wasapproximately 7 times that found in humans after administration of atherapeutically relevant dose. The results from the human studies seemto indicate a small increase in BP_(ND), i.e. a decrease in serotoninlevel upon escitalopram administration. Escitalopram was dosed in atherapeutically relevant amount. The only projection in which anincrease in serotonin level was indicated was RN, and this increase didnot reach significance.

A similar study has been conducted in humans to measure the effect onserotonin levels in the brain upon acute administration of the SSRIcitalopram [Mol Psych 17, 1254-1260, 2012]. This study used [¹¹C]CUMIwhich is a 5-HT_(1A) receptor specific PET ligand. The changes inBP_(ND) shown below indicate a modest increase in serotonin level in DRand a modest decrease in serotonin level in FC, HC and OC of which onlythe decrease in FC reached significance.

Region ΔBP_(ND) (% of baseline) p value FC 6.5 0.006 HC 5.5 0.56 OC 2.90.18 DR −2.7 0.03

The above discussed experimental observations for citalopram andescitalopram are in line with the clinical experience with thesecompounds, i.e. that a lag-time normally exists between the initiationof treatment and an observation of a clinical effect.

The study reported in Example 1 is similar to those discussed above andcompares the change in BP_(ND), i.e. the change in serotonin in relevantparts of the brain following administration of clinically relevant dosesof vortioxetine and citalopram to monkeys.

Vortioxetine was tested at two different dose levels (0.3 mg/kg and 1.0mg/kg) which levels span the SERT occupancy reached at clinicallyrelevant doses. Citalopram was tested at a single dose level (0.3 mg/kg)which was also shown to result in a clinically relevant SERT occupancy.Vortioxetine at both doses produced a much larger reduction in BP_(ND),i.e. an increase in serotonin, compared to citalopram, and also comparedto what has previously been observed with escitalopram and citalopram.In fact, citalopram in the present study in all but one projection areagives rise to a decrease in serotonin level. For vortioxetine at thehigh dose the increase in serotonin reaches significance in allprojection areas investigated. This shows that vortioxetine, contrary toother serotonin reuptake inhibitors investigated, gives rise to a large(and dose dependent) increase in serotonin upon acute IV administration.

From this observation, it is concluded that vortioxetine administered ina way that ensures clinically relevant plasma levels are achieved fastand subsequently maintained will result in a fast onset of action.

A fast increase in plasma level of vortioxetine may be achieved inseveral ways that avoids absorption through the intestines including IVadministration, nasal administration, rectal administration buccaladministration and sublingual administration. In particular IVadministration but also nasal and rectal administration may beinconvenient to the patient as part of a long-term treatment, that is atreatment with the aim to maintain a therapeutically relevantvortioxetine plasma level for weeks, months or even years. Theseadministration forms may therefore conveniently be combined with otheradministration forms, e.g. oral administration in a way so that aclinically relevant plasma level is initially achieved fast usingsimultaneous administration as disclosed herein and wherein said plasmalevel is subsequently maintained using oral administration.

The above fast onset hypothesis was tested in a clinical trial reportedin Example 3. Patients treated with placebo IV on day 0 and oralvortioxetine on day 0 to day 14 were compared to patients treated withvortioxetine IV on day 0 and oral vortioxetine on day 0 to day 14 in adouble-blind/double dummy study. The results show a marked response toboth treatment arms. Moreover, the results show that early in the study(day 1-7) patients in the vortioxetine IV arm experience a faster andlarger response compared to the patients in the placebo IV arm. Later inthe study, i.e. at day 14 the difference between the two armsdisappears. That the responses in the two treatment arms converge latein the study is expected because the effects of the IV administrationearly in the study (day 0) eventually will fade. The results from thisclinical study confirm the fast on-set hypothesis build on the PETmonkey data, namely that a vortioxetine dosing regimen that results in afast increase in the vortioxetine plasma level to steady-state level(for standard oral treatment) provides a faster onset of ananti-depressant effect. More specifically, the result in Example 3 showthat a once daily oral dose of vortioxetine of a pharmaceuticallyacceptable salt thereof administered simultaneously with a secondpharmaceutical composition comprising vortioxetine of a pharmaceuticallyacceptable salts thereof (e.g. single IV dose) where the combinedadministration achieves a steady-state plasma level of vortioxetine fastwhich steady-state level is essentially the same as the vortioxetineplasma steady-state level achieved by the administration of once-dailyoral vortioxetine alone will result in fast onset of an anti-depressiveeffect. The results obtained in Example 3 show that a combination of asingle IV dose of vortioxetine followed by oral administration ofvortioxetine gives rise to a faster and larger anti-depressant effectthan what has previously been experienced with other antidepressants,i.e. citalopram in similar settings—see J Affect Dis, 49, 203-210, 1998and J Affect Dis, 58, 201-209, 2000.

In one embodiment, the invention provides a method for the treatment ofdepression, said method comprising the simultaneous administration oftwo pharmaceutical compositions to a patient in need thereof, whereinthe first pharmaceutical composition is a composition comprisingvortioxetine or a pharmaceutically acceptable salt thereof for oncedaily oral administration, and the second pharmaceutical composition isa composition comprising vortioxetine or a pharmaceutically acceptablesalt thereof which together with said first composition achieves asteady-state plasma level of vortioxetine in said patient within 36hours from said simultaneous administration which steady-state plasmalevel is essentially the same as the steady-state vortioxetine plasmalevel achieved by the administration to said patient of said firstcomposition alone. In one embodiment, the administration of said secondcomposition takes places a limited number of times, such as 1, 2 or 3times, such as 1 time.

In one embodiment, the invention relates to an oral pharmaceuticalcomposition comprising vortioxetine or a pharmaceutically acceptablesalt thereof for once daily oral administration for use in the treatmentof depression wherein said oral pharmaceutical composition issimultaneously administered to a patient in need thereof with apharmaceutical composition comprising vortioxetine or a pharmaceuticallyacceptable salt thereof and wherein said simultaneous administrationachieves a steady-state vortioxetine plasma level within 36 hours fromsaid simultaneous administration in said patient which steady-statevortioxetine plasma level is essentially the same as the steady-statevortioxetine plasma level achieved by the administration to said patientof said oral pharmaceutical composition alone. In one embodiment, theadministration of said pharmaceutical composition takes places a limitednumber of times, such as 1, 2 or 3 times, such as 1 time.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising vortioxetine or a pharmaceutically acceptable salt thereoffor use in the treatment of depression wherein said pharmaceuticalcomposition is simultaneously administered to a patient in need thereofwith an oral pharmaceutical composition comprising vortioxetine or apharmaceutically acceptable salt thereof for once daily administrationwherein said simultaneous administration achieves a steady-statevortioxetine plasma level within 36 hours from said simultaneousadministration in said patient which steady-state vortioxetine plasmalevel is essentially the same as the steady-state vortioxetine plasmalevel achieved by the administration to said patient of said oralpharmaceutical composition alone. In one embodiment, the administrationof said pharmaceutical composition takes places a limited number oftimes, such as 1, 2 or 3 times, such as 1 time.

In one embodiment, the invention relates to two pharmaceuticalcompositions for use in a method for the treatment of depression whichcompositions are simultaneously administered to a patient in needthereof, wherein the first pharmaceutical composition is a compositioncomprising vortioxetine or a pharmaceutically acceptable salt thereoffor once daily oral administration and the second pharmaceuticalcomposition is a composition comprising vortioxetine or apharmaceutically acceptable salt thereof which together with said firstcomposition achieves a steady-state plasma level of vortioxetine in saidpatient within 36 hours from said simultaneous administration whichsteady-state vortioxetine plasma level is essentially the same as thesteady-state vortioxetine plasma level achieved by the administration tosaid patient of said first composition alone. In one embodiment, theadministration of said second composition takes places a limited numberof times, such as 1, 2 or 3 times, such as 1 time.

In one embodiment, the invention relates to the use of vortioxetine or apharmaceutically acceptable salt thereof in the manufacture of a firstpharmaceutical composition for once daily oral administration for thetreatment of depression, wherein said first pharmaceutical compositionis administered to a patient simultaneous with a second pharmaceuticalcomposition comprising vortioxetine or a pharmaceutically acceptablesalt thereof and wherein said simultaneous administration achieves asteady-state vortioxetine plasma level within 36 hours from saidsimultaneous administration in said patient which steady-statevortioxetine plasma level is essentially the same as the steady-statevortioxetine plasma level achieved by the administration to said patientof said first composition alone. In one embodiment, the administrationof said second composition takes places a limited number of times, suchas 1, 2 or 3 times, such as 1 time.

In one embodiment, the invention relates to the use of vortioxetine or apharmaceutically acceptable salt thereof in the manufacture of apharmaceutical composition for the treatment of depression, wherein saidpharmaceutical composition is administered to a patient simultaneouslywith a once daily oral pharmaceutical composition comprisingvortioxetine or a pharmaceutically acceptable salt thereof and whereinsaid simultaneous administration achieves a steady-state vortioxetineplasma level in said patient within 36 hours from said simultaneousadministration which steady-state vortioxetine plasma level isessentially the same as the steady-state vortioxetine level achieved byadministration of said oral pharmaceutical composition to said patientalone. In one embodiment, the administration of said pharmaceuticalcomposition takes places a limited number of times, such as 1, 2 or 3times, such as 1 time.

In one embodiment, the invention relates to a kit comprising a firstpharmaceutical composition which is a composition for once daily oraladministration comprising vortioxetine or a pharmaceutically acceptablesalt thereof and a second pharmaceutical composition which secondpharmaceutical composition is a composition comprising vortioxetine or apharmaceutically acceptable salt thereof, which second composition whenadministered to a patient simultaneously with said first compositionachieves a steady-state plasma level of vortioxetine in said patientwithin 36 hours from said simultaneous administration which steady-statevortioxetine plasma level is essentially the same as the steady-statevortioxetine plasma level achieved by the administration to said patientof said first composition alone.

In one embodiment, “simultaneous” or “simultaneously” is intended toindicate that the initiation of the administration of the twocompositions is initiated essentially at the same time such as at thesame day, such as within 8 hours, such as within 6 hours, such as within2 hours of each other.

Whereas the composition for oral administration of the present inventionis intended for continued or long-term treatment, the second compositionof the present invention is only administered a few times, such as 1, 2or 3 times at the start of the treatment.

Upon multiple oral administration of a drug, such as vortioxetine, thedrug is absorbed from the intestines at a certain rate and once in theblood (or plasma) eliminated though metabolic processes. In the presentcontext, “steady-state plasma level” is intended to indicate the plasmalevel at a point in time (after multiple administrations) where the drugabsorption is in equilibrium with drug elimination. Because plasma drugconcentrations fluctuate (also at steady-state), the steady-state plasmalevel is conveniently stated as the plasma concentration integrated overtime, also referred to as area under the curve (AUC). For a drug, suchas vortioxetine with once daily oral administration, AUC for a 24 hourperiod (AUC₀₋₂₄) is conveniently used.

The steady-state plasma level of vortioxetine upon once daily oraladministration of 5 mg, 10 mg, 15 mg and 20 mg vortioxetine is found tobe 161 ng h/ml, 323 ng h/ml, 484 ng h/ml and 645 ng h/ml, respectively(median AUC₀₋₂₄). In addition, the following 95% prediction intervalswere calculated: 68; 406 ng h/ml for 5 mg/day; 137; 812 ng h/ml for 10mg/day; 205; 1219 ng h/ml for 15 mg/day; and 273; 1625 ng h/ml for 20mg/day. [Basic &Clin Pharmacol & Tox, 115, 552-559, 2014]. With oncedaily oral vortioxetine administration steady-state plasma concentrationof vortioxetine is achieved after approximately 8 days [Basic & ClinPharmacol & Tox, 111, 198,205, 2012].

An element of the present invention is the simultaneous administrationof two pharmaceutical compositions to a patient in need thereof, whereinthe first pharmaceutical composition is a composition comprisingvortioxetine or a pharmaceutically acceptable salt thereof for oncedaily oral administration, and the second pharmaceutical composition isa composition comprising vortioxetine or a pharmaceutically acceptablesalt thereof aiming at achieving a steady-state plasma level ofvortioxetine in said patient within 36 hours from said simultaneousadministration which steady-state plasma level is essentially the sameas the steady-state vortioxetine plasma level achieved by theadministration to said patient of said first composition alone. In oneembodiment, said steady-state level is achieved within 24 hours fromsaid simultaneous administration, such as with 18 hours, such as within12 hours.

In one embodiment, the oral composition of the present inventioncomprising vortioxetine or a pharmaceutically acceptable salt thereofcomprises 5 mg-20 mg vortioxetine, such as 5 mg, 10 mg, 15 mg or 20 mgvortioxetine.

In one embodiment, the invention provides a method for the treatment ofdepression, said method comprising the simultaneous administration oftwo pharmaceutical compositions to a patient in need thereof, whereinthe first pharmaceutical composition is a composition comprising 5 mg-20mg vortioxetine or a pharmaceutically acceptable salt thereof for oncedaily oral administration, and the second pharmaceutical composition isa composition comprising vortioxetine or a pharmaceutically acceptablesalt thereof which together with said first composition achieves asteady-state plasma level of vortioxetine in said patient within 36hours, such as within 24 or 18 or 12 hours from said simultaneousadministration between 68 ng h/ml and 1625 ng h/ml, such as between 150ng h/ml and 700 ng h/ml (AUC₀₋₂₄). In one embodiment, said firstpharmaceutical composition comprises 5 mg vortioxetine or apharmaceutically acceptable salt thereof and the steady-statevortioxetine plasma level is between 68 ng h/ml and 406 ng h/ml, such asbetween 150 ng h/ml and 170 ng h/ml, such as between 155 ng h/ml and 165ng h/ml. In one embodiment, said first pharmaceutical compositioncomprises 10 mg vortioxetine or a pharmaceutically acceptable saltthereof and the steady-state vortioxetine plasma level is between 137 ngh/ml and 812 ng h/ml, such as between 145 ng ml/h and 315 ng h/ml, suchas between 200 ng h/ml and 300 ng h/ml or between 300 ng h/ml and 340 ngh/ml, such as between 310 ng h/ml and 330 ng h/ml. In one embodiment,said first pharmaceutical composition comprises 15 mg vortioxetine or apharmaceutically acceptable salt thereof and the steady-statevortioxetine plasma level is between 205 ng h/ml and 1219 ng h/ml, suchas between 460 ng h/ml and 510 ng h/ml, such as between 470 ng h/ml and500 ng h/ml. In one embodiment, said first pharmaceutical compositioncomprises 20 mg vortioxetine or a pharmaceutically acceptable saltthereof and the steady-state vortioxetine plasma level is between 273 ngh/ml and 1625 ng h/ml, such as between 600 ng h/ml and 700 ng h/ml, suchas between 630 ng h/ml and 660 ng h/ml.

In one embodiment, the invention relates to an oral pharmaceuticalcomposition comprising 5 mg-20 mg vortioxetine or a pharmaceuticallyacceptable salt thereof for once daily oral administration for use inthe treatment of depression wherein said oral pharmaceutical compositionis simultaneously administered to a patient in need thereof with apharmaceutical composition comprising vortioxetine or a pharmaceuticallyacceptable salt thereof and wherein said simultaneous administrationachieves a steady-state vortioxetine plasma level within 36 hours, suchas within 24 or 18 or 12 hours from said simultaneous administration insaid patient between 68 ng h/ml and 1625 ng h/ml, such as between 150 ngh/ml and 700 ng h/ml (AUC₀₋₂₄). In one embodiment, said oralpharmaceutical composition comprises 5 mg vortioxetine or apharmaceutically acceptable salt thereof and the steady-statevortioxetine plasma level is between 68 ng h/ml and 406 ng h/ml, such asbetween 150 ng h/ml and 170 ng h/ml, such as between 155 ng h/ml and 165ng h/ml. In one embodiment, said oral pharmaceutical compositioncomprises 10 mg vortioxetine or a pharmaceutically acceptable saltthereof and the steady-state vortioxetine plasma level is between 137 ngh/ml and 812 ng h/ml, such as between 145 ng h/ml and 315 ng h/ml ngh/ml, such as between 200 ng h/ml and 300 ng h/ml or between 300 ng h/mland 340 ng h/ml, such as between 310 ng h/ml and 330 ng h/ml. In oneembodiment, said oral pharmaceutical composition comprises 15 mgvortioxetine or a pharmaceutically acceptable salt thereof and thesteady-state vortioxetine plasma level is between 295 ng h/ml and 1219ng h/ml, such as between 460 ng h/ml and 510 ng h/ml, such as between470 ng h/ml and 500 ng h/ml. In one embodiment, said oral pharmaceuticalcomposition comprises 20 mg vortioxetine or a pharmaceuticallyacceptable salt thereof and the steady-state vortioxetine plasma levelis between 273 ng h/ml and 1625 ng h/ml, such as between 600 ng h/ml and700 ng h/ml, such as between 630 ng h/ml and 660 ng h/ml.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising vortioxetine or a pharmaceutically acceptable salt thereoffor use in the treatment of depression wherein said pharmaceuticalcomposition is simultaneously administered to a patient in need thereofwith an oral pharmaceutical composition comprising 5 mg-20 mgvortioxetine or a pharmaceutically acceptable salt thereof for oncedaily administration wherein said simultaneous administration achieves asteady-state vortioxetine plasma level within 36 hours, such as within24 or 18 or 12 hours from said simultaneous administration in saidpatient which steady-state vortioxetine plasma level between 68 ng h/mland 1625 ng h/ml, such as between 150 ng h/ml and 700 ng h/ml (AUC₀₋₂₄).In one embodiment, said oral pharmaceutical composition comprises 5 mgvortioxetine or a pharmaceutically acceptable salt thereof and thesteady-state vortioxetine plasma level is between 68 ng h/ml and 406 ngh/ml, such as between 150 ng h/ml and 170 ng h/ml, such as between 155ng h/ml and 165 ng h/ml. In one embodiment, said oral pharmaceuticalcomposition comprises 10 mg vortioxetine or a pharmaceuticallyacceptable salt thereof and the steady-state vortioxetine plasma levelis between 137 ng h/ml and 812 ng h/ml, such as between 145 ng h/ml and315 ng h/ml, such as between 200 ng h/ml and 300 ng h/ml, or between 300ng h/ml and 340 ng h/ml, such as between 310 ng h/ml and 330 ng h/ml. Inone embodiment, said oral pharmaceutical composition comprises 15 mgvortioxetine or a pharmaceutically acceptable salt thereof and thesteady-state vortioxetine plasma level is between 205 ng h/ml and 1219ng h/ml, such as between 460 ng h/ml and 510 ng h/ml, such as between470 ng h/ml and 500 ng h/ml. In one embodiment, said oral pharmaceuticalcomposition comprises 20 mg vortioxetine or a pharmaceuticallyacceptable salt thereof and the steady-state vortioxetine plasma levelis between 273 ng h/ml and 1625 ng h/ml, such as between 600 ng h/ml and700 ng h/ml, such as between 630 ng h/ml and 660 ng h/ml.

In one embodiment, the invention relates to two pharmaceuticalcompositions for use in a method for the treatment of depression whichcompositions are simultaneously administered to a patient in needthereof, wherein said first pharmaceutical composition is a compositioncomprising 5-20 mg vortioxetine or a pharmaceutically acceptable saltthereof for once daily oral administration and the second pharmaceuticalcomposition is a composition comprising vortioxetine or apharmaceutically acceptable salt thereof which together with said firstcomposition achieves a steady-state plasma level of vortioxetine in saidpatient within 36 hours, such as within 24 or 18 or 12 hours from saidsimultaneous administration between 68 ng h/ml and 1625 ng h/ml, such asbetween 150 ng h/ml and 700 ng h/ml (AUC₀₋₂₄). In one embodiment, saidfirst pharmaceutical composition comprises 5 mg vortioxetine or apharmaceutically acceptable salt thereof and the steady-statevortioxetine plasma level is between 68 ng h/ml and 406 ng h/ml, such asbetween 150 ng h/ml and 170 ng h/ml, such as between 155 ng h/ml and 165ng h/ml. In one embodiment, said first pharmaceutical compositioncomprises 10 mg vortioxetine or a pharmaceutically acceptable saltthereof and the steady-state vortioxetine plasma level is between 137 ngh/ml and 812 ng h/ml, such as between 145 ng h/ml and 315 ng g/ml, suchas between 200 ng h/ml and 300 ng h/ml or between 300 ng h/ml and 340 ngh/ml, such as between 310 ng h/ml and 330 ng h/ml. In one embodiment,said first pharmaceutical composition comprises 15 mg vortioxetine or apharmaceutically acceptable salt thereof and the steady-statevortioxetine plasma level is between 205 ng h/ml and 1219 ng h/ml, suchas between 460 ng h/ml and 510 ng h/ml, such as between 470 ng h/ml and500 ng h/ml. In one embodiment, said first pharmaceutical compositioncomprises 20 mg vortioxetine or a pharmaceutically acceptable saltthereof and the steady-state vortioxetine plasma level is between 273 ngh/ml and 1625 ng h/ml, such as between 600 ng h/ml and 700 ng h/ml, suchas between 630 ng h/ml and 660 ng h/ml.

In one embodiment, the invention relates to the use of vortioxetine or apharmaceutically acceptable salt thereof in the manufacture of a firstpharmaceutical composition for once daily oral administration comprising5-20 mg vortioxetine for the treatment of depression, wherein said firstpharmaceutical composition is administered to a patient simultaneouslywith a second pharmaceutical composition which second pharmaceuticalcomposition is a composition comprising vortioxetine or apharmaceutically acceptable salts thereof which together with said firstcomposition achieves a steady-state vortioxetine plasma level within 36hours, such as with 24, 18 or 12 hours from said simultaneousadministration in said patient between 68 ng h/ml and 1625 ng h/ml, suchas between 150 ng h/ml and 700 ng h/ml (AUC₀₋₂₄). In one embodiment,said first pharmaceutical composition comprises 5 mg vortioxetine or apharmaceutically acceptable salt thereof and the steady-statevortioxetine plasma level is between 68 ng h/ml and 406 ng h/ml, such asbetween 150 ng h/ml and 170 ng h/ml, such as between 155 ng h/ml and 165ng h/ml. In one embodiment, said first pharmaceutical compositioncomprises 10 mg vortioxetine or a pharmaceutically acceptable saltthereof and the steady-state vortioxetine plasma level is between 137 ngh/ml and 812 ng h/ml, such as between 145 ng h/ml and 315 ng h/ml, suchas between 200 ng h/ml and 300 ng h/ml or between 300 ng h/ml and 340 ngh/ml, such as between 310 ng h/ml and 330 ng h/ml. In one embodiment,said first pharmaceutical composition comprises 15 mg vortioxetine or apharmaceutically acceptable salt thereof and the steady-statevortioxetine plasma level is between 205 ng h/ml and 1219 ng h/ml, suchas between 460 ng h/ml and 510 ng h/ml, such as between 470 ng h/ml and500 ng h/ml. In one embodiment, said first pharmaceutical compositioncomprises 20 mg vortioxetine or a pharmaceutically acceptable saltthereof and the steady-state vortioxetine plasma level is between 273 ngh/ml and 1625 ng h/ml, such as between 600 ng h/ml and 700 ng h/ml, suchas between 630 ng h/ml and 660 ng h/ml.

In one embodiment, the invention relates to the use of vortioxetine or apharmaceutically acceptable salt thereof in the manufacture of apharmaceutical composition for the treatment of depression, wherein saidpharmaceutical composition is administered to a patient simultaneouslywith a once daily oral pharmaceutical composition comprising 5-20 mgvortioxetine or a pharmaceutically acceptable salt thereof and whereinsaid simultaneous administration achieves a steady-state vortioxetineplasma level in said patient within 36 hours, such as within 24, 18 or12 hours from said simultaneous administration between 68 ng h/ml and1625 ng h/ml, such as between 150 ng h/ml and 700 ng h/ml (AUC₀₋₂₄). Inone embodiment, said oral pharmaceutical composition comprises 5 mgvortioxetine or a pharmaceutically acceptable salt thereof and thesteady-state vortioxetine plasma level is between 68 ng h/ml and 406 406ng h/ml, such as between 150 ng h/ml and 170 ng h/ml, such as between155 ng h/ml and 165 ng h/ml. In one embodiment, said oral pharmaceuticalcomposition comprises 10 mg vortioxetine or a pharmaceuticallyacceptable salt thereof and the steady-state vortioxetine plasma levelis between 137 ng h/ml and 812 ng h/ml, such as between 145 ng h/ml and315 ng h/ml, such as between 200 ng h/ml and 300 ng h/ml or between 300ng h/ml and 340 ng h/ml, such as between 310 ng h/ml and 330 ng h/ml. Inone embodiment, said oral pharmaceutical composition comprises 15 mgvortioxetine or a pharmaceutically acceptable salt thereof and thesteady-state vortioxetine plasma level is between 205 ng h/ml and 1219ng h/ml, such as between 460 ng h/ml and 510 ng h/ml, such as between470 ng h/ml and 500 ng h/ml. In one embodiment, said oral pharmaceuticalcomposition comprises 20 mg vortioxetine or a pharmaceuticallyacceptable salt thereof and the steady-state vortioxetine plasma levelis between 273 ng h/ml and 1625 ng h/ml, such as between 600 ng h/ml and700 ng h/ml, such as between 630 ng h/ml and 660 ng h/ml.

As shown in Example 2, the simultaneous administration of 5 mgvortioxetine once daily per oral and a single dose of 8.5 mgvortioxetine intravenously administered over 1 hour achieves asteady-state vortioxetine plasma level which is similar to that achievedfrom an oral administration of 5 mg vortioxetine alone within 24 hoursfrom said simultaneous administration. Similarly, the simultaneousadministration of 10 mg vortioxetine once daily per oral and a singledose of 17 mg vortioxetine intravenously administered over 1 hourachieves a steady-state vortioxetine plasma level which is similar tothat achieved from an oral administration of 10 mg vortioxetine alonewithin 24 hours from said simultaneous administration. Similarly, thesimultaneous administration of 15 mg vortioxetine once daily per oraland a single dose of 25.5 mg vortioxetine intravenously administeredover 1 hour achieves a steady-state vortioxetine plasma level which issimilar to that achieved from an oral administration of 15 mgvortioxetine alone within 24 hours from said simultaneousadministration. Similarly, the simultaneous administration of 20 mgvortioxetine once daily per oral and a single dose of 34 mg vortioxetineintravenously administered over 1 hour achieves a steady-statevortioxetine plasma level which is similar to that achieved from an oraladministration of 20 mg vortioxetine alone within 24 hours from saidsimultaneous administration.

In one embodiment, the present invention provides a method for thetreatment of depression, said method comprising the oral administrationof 5 mg vortioxetine or a pharmaceutically acceptable salt thereof oncedaily and a single dose of 5 mg-12 mg, such as 6 mg-10 mg, such as 8.5mg vortioxetine or a pharmaceutically acceptable salt thereofintravenously administered simultaneously with said oral administrationto a patient in need thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides a method for thetreatment of depression, said method comprising the oral administrationof 10 mg vortioxetine or a pharmaceutically acceptable salt thereof oncedaily and a single dose of 14 mg-20 mg, such as 15 mg-19 mg, such as 17mg vortioxetine or a pharmaceutically acceptable salt thereofintravenously administered simultaneously with said oral administrationto a patient in need thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides a method for thetreatment of depression, said method comprising the oral administrationof 15 mg vortioxetine or a pharmaceutically acceptable salt thereof oncedaily and a single dose of 20 mg-30 mg, such as 22 mg-28 mg, such as25.5 mg vortioxetine or a pharmaceutically acceptable salt thereofintravenously administered simultaneously with said oral administrationto a patient in need thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides a method for thetreatment of depression, said method comprising the oral administrationof 20 mg vortioxetine or a pharmaceutically acceptable salt thereof oncedaily and a single dose of 30 mg-40 mg, such as 32 mg-36 mg, such as 34mg vortioxetine or a pharmaceutically acceptable salt thereofintravenously administered simultaneously with said oral administrationto a patient in need thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 5 mg vortioxetineor a pharmaceutically acceptable salt thereof for use in the treatmentof depression wherein said oral pharmaceutical composition is forsimultaneous administration with a single dose of 5 mg-12 mg, such as 6mg-10 mg, such as 8.5 mg vortioxetine or a pharmaceutically acceptablesalt thereof intravenously administered. In one embodiment, said singleIV dose is administered over 15 minutes to 6 hours, such as 30 minutesto 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 10 mg vortioxetineor a pharmaceutically acceptable salt thereof for use in the treatmentof depression wherein said oral pharmaceutical composition is forsimultaneous administration with a single dose of 14 mg-20 mg, such as15 mg-19 mg, such as 17 mg vortioxetine or a pharmaceutically acceptablesalt thereof intravenously administered. In one embodiment, said singleIV dose is administered over 15 minutes to 6 hours, such as 30 minutesto 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 15 mg vortioxetineor a pharmaceutically acceptable salt thereof for use in the treatmentof depression wherein said oral pharmaceutical composition is forsimultaneous administration with a single dose of 20 mg-30 mg, such as22 mg-28 mg, such as 25.5 mg vortioxetine or a pharmaceuticallyacceptable salt thereof intravenously administered. In one embodiment,said single IV dose is administered over 15 minutes to 6 hours, such as30 minutes to 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 20 mg vortioxetineor a pharmaceutically acceptable salt thereof for use in the treatmentof depression wherein said oral pharmaceutical composition is forsimultaneous administration with a single dose of 30 mg-40 mg, such as32 mg-36 mg, such as 34 mg vortioxetine or a pharmaceutically acceptablesalt thereof intravenously administered. In one embodiment, said singleIV dose is administered over 15 minutes to 6 hours, such as 30 minutesto 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the invention provides a pharmaceutical compositioncomprising 5 mg-12 mg, such as 6 mg-10 mg, such as 8.5 mg vortioxetineor a pharmaceutically acceptable salt for single intravenousadministration wherein said pharmaceutical composition is forsimultaneous administration with a once daily oral pharmaceuticalcomposition comprising 5 mg vortioxetine or a pharmaceuticallyacceptable salt thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the invention provides a pharmaceutical compositioncomprising 14 mg-20 mg, such as 15 mg-19 mg, such as 17 mg vortioxetineor a pharmaceutically acceptable salt for single intravenousadministration wherein said pharmaceutical composition is forsimultaneous administration with a once daily oral pharmaceuticalcomposition comprising 10 mg vortioxetine or a pharmaceuticallyacceptable salt thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the invention provides a pharmaceutical compositioncomprising 20 mg-30 mg, such as 22 mg-28 mg, such as 25.5 mgvortioxetine or a pharmaceutically acceptable salt for singleintravenous administration wherein said pharmaceutical composition isfor simultaneous administration with a once daily oral pharmaceuticalcomposition comprising 15 mg vortioxetine or a pharmaceuticallyacceptable salt thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the invention provides a pharmaceutical compositioncomprising 30 mg-40 mg, such as 32 mg-36 mg, such as 34 mg vortioxetineor a pharmaceutically acceptable salt for single intravenousadministration wherein said pharmaceutical composition is forsimultaneous administration with a once daily oral pharmaceuticalcomposition comprising 20 mg vortioxetine or a pharmaceuticallyacceptable salt thereof. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 5 mg vortioxetineor a pharmaceutically acceptable salt thereof and a single dose of 5mg-12 mg, such as 6 mg-10 mg, such as 8.5 mg vortioxetine or apharmaceutically acceptable salt thereof intravenously administeredsimultaneously with said oral administration for use in a method in thetreatment of depression. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 10 mg vortioxetineor a pharmaceutically acceptable salt thereof and a single dose of 14mg-20 mg, such as 15 mg-19 mg, such as 17 mg vortioxetine or apharmaceutically acceptable salt thereof intravenously administeredsimultaneously with said oral administration for use in a method for thetreatment of depression. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 15 mg vortioxetineor a pharmaceutically acceptable salt thereof and a single dose of 20mg-30 mg, such as 22 mg-28 mg, such as 25.5 mg vortioxetine or apharmaceutically acceptable salt thereof intravenously administeredsimultaneously with said oral administration for use in a method for thetreatment of depression. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides an oral pharmaceuticalcomposition for once daily administration comprising 20 mg vortioxetineor a pharmaceutically acceptable salt thereof and a single dose of 30mg-40 mg, such as 32 mg-36 mg, such as 34 mg vortioxetine or apharmaceutically acceptable salt thereof intravenously administeredsimultaneously with said oral administration for use in a method for thetreatment of depression. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of an oral pharmaceutical composition for once dailyadministration comprising 5 mg vortioxetine for the treatment ofdepression, wherein said oral pharmaceutical composition is administeredto a patient simultaneously with a single dose IV pharmaceuticalcomposition comprising 5 mg-12 mg, such as 6 mg-10 mg, such as 8.5 mgvortioxetine or a pharmaceutically acceptable salt. In one embodiment,said single IV dose is administered over 15 minutes to 6 hours, such as30 minutes to 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of an oral pharmaceutical composition for once dailyadministration comprising 10 mg vortioxetine for the treatment ofdepression, wherein said oral pharmaceutical composition is administeredto a patient simultaneously with a single dose IV pharmaceuticalcomposition comprising 14 mg-20 mg, such as 15 mg-19 mg, such as 17 mgvortioxetine or a pharmaceutically acceptable salt. In one embodiment,said single IV dose is administered over 15 minutes to 6 hours, such as30 minutes to 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of an oral pharmaceutical composition for once dailyadministration comprising 15 mg vortioxetine for the treatment ofdepression, wherein said oral pharmaceutical composition is administeredto a patient simultaneously with a single dose IV pharmaceuticalcomposition comprising 20 mg-30 mg, such as 22 mg-28 mg, such as 25.5 mgvortioxetine or a pharmaceutically acceptable salt. In one embodiment,said single IV dose is administered over 15 minutes to 6 hours, such as30 minutes to 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of an oral pharmaceutical composition for once dailyadministration comprising 20 mg vortioxetine for the treatment ofdepression, wherein said oral pharmaceutical composition is administeredto a patient simultaneously with a single dose IV pharmaceuticalcomposition comprising 30 mg-40 mg, such as 32 mg-36 mg, such as 34 mgvortioxetine or a pharmaceutically acceptable salt. In one embodiment,said single IV dose is administered over 15 minutes to 6 hours, such as30 minutes to 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of a pharmaceutical composition for IV administrationcomprising 5 mg-12 mg, such as 6 mg-10 mg, such as 8.5 mg vortioxetinethe treatment of depression, wherein said IV composition is administeredsimultaneously with an oral pharmaceutical composition for once dailyadministration comprising 5 mg vortioxetine or a pharmaceuticallyacceptable salt thereof for. In one embodiment, said single IV dose isadministered over 15 minutes to 6 hours, such as 30 minutes to 3 hours,such as 1-2 hours. In particular, said IV dose is administeredsimultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of a pharmaceutical composition for IV administrationcomprising 14 mg-20 mg, such as 15 mg-19 mg, such as 17 mg vortioxetinefor the treatment of depression, wherein said IV composition isadministered simultaneously with an oral pharmaceutical composition foronce daily administration comprising 10 mg vortioxetine or apharmaceutically acceptable salt thereof. In one embodiment, said singleIV dose is administered over 15 minutes to 6 hours, such as 30 minutesto 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of a pharmaceutical composition for IV administrationcomprising 20 mg-30 mg, such as 22 mg-28 mg, such as 25.5 mgvortioxetine for the treatment of depression, wherein said IVcomposition is administered simultaneously with an oral pharmaceuticalcomposition for once daily administration comprising 15 mg vortioxetineor a pharmaceutically acceptable salt thereof. In one embodiment, saidsingle IV dose is administered over 15 minutes to 6 hours, such as 30minutes to 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides the use ofvortioxetine or a pharmaceutically acceptable salt thereof in themanufacture of a pharmaceutical composition for IV administrationcomprising 30 mg-40 mg, such as 32 mg-36 mg, such as 34 mg vortioxetinefor the treatment of depression, wherein said IV composition isadministered simultaneously with an oral pharmaceutical composition foronce daily administration comprising 20 mg vortioxetine or apharmaceutically acceptable salt thereof. In one embodiment, said singleIV dose is administered over 15 minutes to 6 hours, such as 30 minutesto 3 hours, such as 1-2 hours. In particular, said IV dose isadministered simultaneously with the first of said oral administrations.Alternatively, said IV dose is administered very quickly to the patientsas an injection within a few seconds to a few minutes, such as up to 15minutes.

In one embodiment, the present invention provides a kit comprising anoral pharmaceutical composition for once daily administration comprising5 mg-20 mg vortioxetine or a pharmaceutical acceptable salt thereof anda pharmaceutical composition for IV administration comprising 5 mg-40 mgvortioxetine or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a kit comprising anoral pharmaceutical composition for once daily administration comprising5 mg vortioxetine or a pharmaceutical acceptable salt thereof and apharmaceutical composition for IV administration comprising 5 mg-12 mg,such as 6 mg-10 mg, such as 8.5 mg vortioxetine or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the present invention provides a kit comprising anoral pharmaceutical composition for once daily administration comprising10 mg vortioxetine or a pharmaceutical acceptable salt thereof and apharmaceutical composition for IV administration comprising 14 mg-20 mg,such as 15 mg-19 mg, such as 17 mg vortioxetine or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the present invention provides a kit comprising anoral pharmaceutical composition for once daily administration comprising15 mg vortioxetine or a pharmaceutical acceptable salt thereof and apharmaceutical composition for IV administration comprising 20 mg-30 mg,such as 22 mg-28 mg, such as 25.5 mg vortioxetine or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the present invention provides a kit comprising anoral pharmaceutical composition for once daily administration comprising20 mg vortioxetine or a pharmaceutical acceptable salt thereof and apharmaceutical composition for IV administration comprising 30 mg-40 mg,such as 32 mg-36 mg, such as 34 mg vortioxetine or a pharmaceuticallyacceptable salt thereof.

As alternatives to IV administration as discussed above otheradministration forms including nasal, buccal, sublingual and rectaladministration may be used. Such administrations forms avoid absorptionthrough the intestines and first-pass metabolism and are as such likelyto result in a rapid increase in vortioxetine level in the plasma. It isan advantage if the bioavailability of vortioxetine as formulated fornasal, buccal, sublingual or rectal administration is high to avoid theneed of having to administer large amounts of vortioxetine to achievethe desired effect. Preferably, the bioavailability (as compared to IVadministration) is above 70%, such as above 80%, such as above 90%. Thedoses for nasal, buccal, sublingual or rectal administration (relativeto the IV doses discussed above) may be adjusted according to the actualbioavailability of the administration form used.

After administration via a nasal, buccal, sublingual or rectal route,vortioxetine is absorbed across mucosa in the nose, mouth or rectum. Thebioavailability of a compound across mucosa may be controlled by thepharmaceutical composition in which the compound is presented. Forexample, the use of muco-adhesive ingredients may prolong the contacttime between the compound and the mucosa and thereby increasebioavailability. Examples of muco-adhesives include polymers, such ascarbomers, chitosans, cellulose and starch derivatives. Absorptionenhancing ingredients may also be used to reversibly modify the barrierproperties of the relevant epithelium to increase bioavailability.Examples of absorption enhancers include surfactants, bile salts andfatty acids, such as oleic acid [Curr Probl Dermatol, 40, 20-35, 2011;Clin Pharmacokinet, 42, 1107-1128, 2003].

The present invention relates to the use of an oral pharmaceuticalcomposition comprising vortioxetine or a pharmaceutically acceptablesalt thereof administered simultaneously with a second pharmaceuticalcomposition comprising vortioxetine or a pharmaceutically acceptablesalt thereof to quickly achieve steady-state vortioxetine plasma levelsimilar to that obtained from the administration of said oralcomposition alone. Both pharmaceutical compositions of the presentinvention may, in addition to the active ingredient, contain apharmaceutically acceptable carriers.

Preparation of pharmaceutical compositions and extensive lists ofcarriers used in pharmaceutical compositions may be found e.g. inRemington, The Science and Practice of Pharmacy, 22^(th) Ed.,Pharmaceutical Press, 2013.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, they can be prepared with coatings.Suitable carriers for oral compositions include lactose, mannitol,microcrystalline cellulose, hydroxypropyl cellulose, sodium starchglycolate, corn starch, potato starch, terra alba, sucrose,cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate,stearic acid and lower alkyl ethers of cellulose.

Tablets may be prepared by mixing vortioxetine or a pharmaceuticallyacceptable salt thereof with ordinary carriers followed by thecompression of the mixture in a conventional tabletting machine. Anyother adjuvants or additives usually used for such purposes such ascolourings, preservation etc. may be used provided that they arecompatible with the active ingredients.

Vortioxetine is available in a commercial oral pharmaceuticalcomposition comprising 5 mg, 10 mg, 15 mg or 20 mg vortioxetine HBr andmannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodiumstarch glycolate, magnesium stearate with a film coating which consistsof hypromellose, titanium dioxide, polyethylene glycol 400, iron oxidered (5 mg, 15 mg, and 20 mg) and iron oxide yellow (10 mg and 15 mg).

A pharmaceutical composition for intravenous administration as used inthe present invention may be an aqueous solution comprising vortioxetineor a pharmaceutically acceptable salt thereof. Such intravenouscomposition may additionally comprise solvents, buffers, surfactant,tonicity agent, preservatives and antioxidants. Examples of solventsinclude ethanol, propylene glycol, glycerol and polyethylene glycol. Thesolubility of vortioxetine or a pharmaceutically acceptable salt thereofmay be enhanced by the addition of a e.g. a co-solvent or cyclodextrinor a derivative thereof. Examples of surfactants include tweens, spansand mono- and diglycerides. Examples of tonicity agents includedextrose, glycerine and sodium chloride. Examples of preservativesinclude ethanol, benzoic acid, sorbic acid, methylparaben, propylparabenand benzylalcohol. Examples of antioxidants include propyl gallate,ascorbic acid and EDTA. It is important that a pharmaceuticalcomposition for intravenous administration is sterile. Such compositionmay either be packaged ready-to-use or as a high-concentrationcomposition which is mixed with e.g. isotonic saline prior to, or aspart of, the intravenous infusion.

An example of a pharmaceutical composition for intravenousadministration is provided below:

Vortioxetine HBr 1.271 mg

Sulfobutyl Ether β-cyclodextrin Sodium 16 mg

Sodium Chloride 9 mg

Water add 1 ml.

A suitable volume of this composition may be mixed with isotonic saline(e.g., 50-500 ml) for intravenous administration.

A pharmaceutical composition for nasal administration where the activeingredient is absorbed via the nasal mucosa is typically an aqueoussolution, emulsion or suspension administered to the nasal cavity indrops or in sprays. A nasal composition is typically formulated to besimilar to nasal secretion with respect to tonicity, pH and viscosity tomaintain normal ciliary action. A pharmaceutical composition for nasaladministration may contain buffers, NaCl or methylcellulose andpreservatives. Pharmaceutical compositions for nasal administration arenormally packaged in dropper or spray bottles.

A pharmaceutical composition comprising vortioxetine or apharmaceutically acceptable salt thereof for buccal including sublingualadministration preferable disintegrate rapidly when inserted into thebuccal pouch or placed under the tongue. The disintegration time uponinsertion into the mouth can normally be extrapolated from the time todisintegrate in water at 37° C., e.g., as described in Remington, TheScience and Practice of Pharmacy, 22^(th) Ed., Pharmaceutical Press,2013 page 968. In the present context, rapid disintegration is intendedto indicate disintegration in water at 37° C. as described above within60 seconds, such as within 30 seconds, such as within 10 seconds.

A pharmaceutical composition for buccal or sublingual administration maycomprise a water soluble or water dispersible carrier, such aspolysaccharides like hydrolysed dextran, dextrin, mannitol, andalginates, or mixtures thereof with other carrier materials likepolyvinyl alcohol, polyvinylpyrrolidine and water-soluble cellulosederivatives, like hydroxypropyl cellulose.

A pharmaceutical composition comprising vortioxetine or apharmaceutically acceptable salt thereof for rectal administration maybe in the form of suppositories, microclysms, soft gelatin rectalcapsules, rectal ointments, sprays and the like. For this purpose,conventional carriers and techniques can be used. As an example, for theformulation of soft gelatin capsules, an oily dispersion of vortioxetineor a pharmaceutically acceptable salt thereof can be used, obtainedusing carriers such as polyethylene glycols, vaseline oil, vegetable andsemisynthetic officinal oils including medium chain saturatedtriglycerides. In order to avoid settling of the ingredients dispersantssuch as polyalcohol fatty acid esters, polyoxyethylene fatty acidesters, polyoxyethylene fatty alcohol esters and, polyoxyethylenesorbitane ester derivatives may be applied.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various compounds of the inventionor particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

EXAMPLES Example 1 PET Monkey Study

Positron Emission Tomography (PET) was used to assess changes in theendogenous serotonin concentration in living rhesus monkeys. Theobjective of the present study was two-fold. A first PET study wasdesigned to determine the dose response relation for vortioxetine- andcitalopram-induced serotonin transporter occupancy in the monkey brainusing the SERT radio-ligand [¹¹C]MADAM. The chemical name for [¹¹C]MADAMis [¹¹C] N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine. Asecond PET study was designed to compare the release capacity ofvortioxetine and citalopram after doses that induce similar SERToccupancy using the 5-HT_(1B) receptor radio-ligand [¹¹C]AZ10419369.

FIG. 1 illustrates the study design used for assessment of serotoninreleasing capacities. A similar study design was applied for assessmentof SERT occupancy.

The SERT occupancy study showed that 0.3 mg/kg and 1.0 mg/kgvortioxetine intravenously administered corresponds to approximately 50%and 80% SERT occupancy, respectively. These occupancy levels correspondsto clinically relevant occupancy levels as measured in PET studies inhealthy subjects [Basic Clin Pharmacol Tox, 110, 401-404, 2012].Similarly, the 0.3 mg/kg citalopram intravenously administeredcorresponds to a SERT occupancy of approximately 83%, which is alsoknown to be clinically relevant [Am J Psych 158, 1843-1849, 2001].

The table below sets out the changes in [¹¹C]AZ10419369-5-HT_(1B)receptor binding potential (BP_(ND)) in various brain regions aftervortioxetine and citalopram administration. The results are shown asmean±standard error for n=3, and * indicates p<0.05 by two-tailed Pairedt-test.

ΔBP_(ND) (% of baseline) Vortioxetine Vortioxetine Citalopram Brainregion 1.0 mg/kg 0.3 mg/kg 0.3 mg/kg Putamen −40.8 ± 7.9* −15.6 ± 8.5 7.3 ± 12.0 Caudate nucleus −47.0 ± 8.0* −23.2 ± 7.4 7.1 ± 7.5 Ventralstriatum −47.7 ± 8.5*  −25.6 ± 5.4*  3.1 ± 10.8 Globus pallidus −41.2 ±6.4* −16.3 ± 5.1 −1.6 ± 9.6   Amygdala  −39.5 ± 11.5*  −12.4 ± 10.5  4.6± 11.6 Hippocampus −27.0 ± 6.8*  −9.4 ± 8.9  5.4 ± 12.5 Frontal gyrus−32.8 ± 9.5*  −8.2 ± 8.2 12.4 ± 9.3  Occipital gyrup −54.1 ± 4.2*  −24.3± 3.2* 15.7 ± 11.1 Thalamus −42.5 ± 7.0*  −23.9 ± 5.0* 0.3 ± 5.6Midbrain −49.4 ± 7.1*  −21.9 ± 3.0* 2.7 ± 5.3 Dorsal raphe nucleus −55.0± 3.3*  −28.3 ± 13.6  −21.2 ± 5.7*   

Example 2 Simulation of Plasma Profiles

A population pharmacokinetic (popPK) model describing the disposition ofvortioxetine is available in the literature together with the exposurelevels (C_(max) and AUC) at steady-state after oral administration[Basic Clin Pharmacol Tox, 115, 552-559, 2014]. The bioavailability ofvortioxetine after oral administration is 75% relative to IVadministration [Basic Clin Pharmacol Toxicol 111, 198-205, 2012]. ThepopPK model together with the oral bioavailability of vortioxetine wasused to calculate which dose of a single IV administered vortioxetineinfused over 1 hour is necessary to simultaneously administer with oncedaily orally administered vortioxetine in order to obtain an exposurelevel within 24 hours corresponding to the steady-state plasma levelthat would have been obtained from the oral administration alone. Thetable below shows the results.

IV dose necessary in order to Orally achieve steady-state vortioxetineadministered plasma level corresponding to orally dose administered dosewithin 24 hours (mg vortioxetine) (mg vortioxetine) 5 8.5 10 17 15 25.520 34

Example 3 Clinical Trial

The clinical effect of simultaneous administration of oral vortioxetineand IV vortioxetine may be assessed in a clinical study as shown here.

In a double-blind study, patients are randomised (1:1) to either of twodose regimes. (1) Vortioxetine 17 mg IV and vortioxetine 10 mg/day(tablet), or (2) placebo IV and vortioxetine 10 mg/day (tablet).Patients enrolled in the study have recurrent major depressive disorderdiagnosed according to DSM-V.

On day 0 patients have 17 mg vortioxetine or placebo IV infused over 2hours. From day 0 to day 14 all patients receive 10 mg/day vortioxetineorally.

Efficacy of the two dose regimes is assessed by the MADRS scalethroughout the study.

In particular, a total of 55 patients (27 and 28 in each treatmentgroup) were recruited to an interventional, prospective, multi-national,multi-site, randomised, double-blind, parallel-group, fixed-dose study.The patients were outpatients with a primary diagnosis of recurrentmajor depressive disorder according to DSM-5™ criteria (classificationcode 296.3x), who had a Montgomery Åsberg Depression Rating Scale(MADRS) total score 30 at the Screening Visit and at the Baseline Visit,were and 65 years of age, had had the current major depressive episodefor months and was an outpatient at a psychiatric setting willing to behospitalised for 24 hours following the Baseline Visit.

The study consisted of a Screening Period—2 to 14-day period fromscreening to randomisation, a Treatment Period—15-day double-blindtreatment period with one initial IV administration of 17 mgvortioxetine or saline and daily oral treatment with vortioxetine 10 mgand a Safety Follow-up Period—4-week period after end of treatment orafter withdrawal from the study.

At the Baseline Visit, patients were equally randomised (1:1) to eitherof the following two dose regimens: vortioxetine 17 mg single dose (IV)and vortioxetine 10 mg/day (tablet) or placebo single dose (IV) andvortioxetine 10 mg/day (tablet).

Patients randomised to the vortioxetine IV dose regimen, received asingle double-blind IV dose of 17 mg vortioxetine, infused over 2 hours,on Day 0 (baseline). Patients randomised to the vortioxetine oral doseregimen received a single double-blind IV dose of placebo (saline),infused over 2 hours, on Day 0. From Day 0 to Day 14, all patients inboth treatment groups also received open labelled 10 mg/day vortioxetineby oral administration (tablets).

Following the IV infusion, patients stayed hospitalised forapproximately 24 hours for close observation. After the hospitalisationperiod, patients continued the study on an outpatient basis.

Efficacy and safety data were collected at Days 0, 1, 3, 7, and 14,including MADRS and clinical global impression (CGI).

As expected, the outcome difference between the two treatment groupsbecame smaller over time as the effect of the active IV dose two weeksearlier levelled off. Table 1 below shows the MADRS readout at day 0 to7. The results show a marked decrease in MADRS scores (i.e. animprovement of the clinical sign of depression) and a faster decrease inthe vortioxetine IV arm.

TABLE 1 Change in MADRS total score day 1-7 Treatment Mean group N(Baseline) Day Mean Difference PBO IV + VOR 28 33.4 1 −5.5 oral 3 −10.37 −13.4 VOR IV + VOR 27 34.6 1 −6.9 −1.4 oral 3 −12.1 −1.7 7 −13.7 −0.3

The full MADRS scale may not be a suitable tool for gauging the earlyonset of anti-depressant effect of a drug because some of the ten itemsaddressed in the MADRS test may require longer assessment time tovalidly assess a given symptom. For example, the MADRS item“Concentration Difficulties” requires that the patient has been exposedto a situation during the treatment where a change in the ability toconcentrate could be identified in order for that item to truly reflecta treatment effect. It has recently been suggested (2017 ASCP AnnualMeeting (Miami Beach, Fla., May 29-Jun. 2, 2017)) that the MADRS items“Apparent sadness”, “Reported sadness”, “Inner tension”, “Pessimisticthoughts” and “Suicidal thoughts” may be a better suited sub-set of theMADRS scale to gauge the short-term effects of an antidepressant. Table2 below shows the effect in the two treatment arms as measured by this5-item MADRS scale.

TABLE 2 Change in 5-item MADRS score day 1-14 Treatment Mean group N(Baseline) Day Mean Difference PBO IV + VOR 28 15.71 1 −3.92 oral 3−6.00 7 −7.03 14 9.21 VOR IV + VOR 27 34.6 1 −5.05 −1.13 oral 3 −6.96−0.96 7 −8.30 −1.27 14 9.37 −0.16

Moreover, Table 3 below depicts the response rate in the two arms, i.e.the fraction of the patients experiencing a more than or equal to 50%reduction on the MADRS scale. The data clearly shows a markedly largerproportion of the patients responding to the vortioxetine IV treatmentearly in the study and that the difference between the two armsdisappears over time.

TABLE 3 % responders (≧50% reduction on MADRS Scale) Day PBO IV + VORoral VOR IV + VOR oral 1 0 3.7 3 14.3 29.6 7 28.6 40.7 14 50.0 48.1

Table 4 below depicts the response rate as measured by the fraction ofthe patients with an improvement on the CGI-I scale of 2 or more. Again,the data shows a markedly faster response to the vortioxetine IVtreatment, and assessed this way the vortioxetine IV treatment arm issuperior also at day 14.

TABLE 4 % responders (CGI-I ≦ 2) Day PBO IV + VOR oral VOR IV + VOR oral1 7.1 18.5 3 39.3 50.0 7 42.9 53.8 14 67.9 73.1

Finally, Table 5 below shows the vortioxetine plasma levels sampledduring the first 24 hours post-dose and at study end. The popPK modelfrom example 2 was used to simulate vortioxetine plasma levels based onthe observed data from Table 5. This simulation shows that AUC₀₋₂₄ atday 0 for the VOR IV+VOR oral treated patients was 251±46 ng h/ml and47±20 ng h/ml for the PBO IV+VOR oral treated patients. The simulationalso shows that AUC₀₋₂₄ at day 14 for the PBO IV+VOR oral treatedpatients is 230±85 ng h/ml. That is, the steady-state plasma level ofvortioxetine achieved from the combined IV and oral vortioxetineadministration the within 24 hours from the first dosing is essentiallythe same as the steady-state vortioxetine plasma level achieved at day14 following the administration of once-daily oral vortioxetine alone inthat period.

TABLE 5 Vortioxetine plasma levels (ng/ml) Visit PBO IV + VOR oral VORIV + VOR oral Day 0, 2 hours 0.56 ± 1.18 11.1 ± 9.3  Day 0, 8 hours 2.8± 1.8 11.0 ± 2.9  Day 0, 24 hours 2.6 ± 1.3 8.6 ± 2.6 Day 14 9.9 ± 5.310.8 ± 7.0 

Overall, the data strongly indicate that patients receiving a singledose IV vortioxetine in combination with oral vortioxetine experience afaster on-set of anti-depressive action than patients receiving placeboIV and oral vortioxetine.

The invention claimed is:
 1. A method for the treatment of depression,said method comprising: simultaneously administering two pharmaceuticalcompositions to a patient in need thereof, wherein the firstpharmaceutical composition is a composition comprising vortioxetine or apharmaceutically acceptable salt thereof for once daily oraladministration, and the second pharmaceutical composition is acomposition comprising vortioxetine or a pharmaceutically acceptablesalt thereof which, together with said first composition, achieves asteady-state plasma level of vortioxetine in said patient within 36hours from said simultaneous administration, which steady-state plasmalevel is essentially the same as the steady-state vortioxetine plasmalevel achieved by the administration to said patient of said firstcomposition alone.
 2. The method of claim 1, wherein said firstpharmaceutical composition comprises 5 mg-20 mg vortioxetine or apharmaceutically acceptable salt thereof, and the second pharmaceuticalcomposition is a composition comprising vortioxetine or apharmaceutically acceptable salt thereof which, together with said firstcomposition, achieves a steady-state plasma level between 68 ng h/ml and1625 ng h/ml vortioxetine in said patient within 24 hours from saidsimultaneous administration.
 3. The method of claim 1, wherein saidsecond pharmaceutical composition is administered intravenously,nasally, buccally, or rectally.
 4. The method of claim 1, wherein saidfirst pharmaceutical composition comprises 5 mg-20 mg vortioxetine or apharmaceutically acceptable salt thereof and said second pharmaceuticalcomposition comprises 5 mg-40 mg vortioxetine or a pharmaceuticallyacceptable salt thereof for intravenous administration to achieve asteady-state plasma level of vortioxetine between 68 ng h/ml and 1625 ngh/ml vortioxetine in said patient within 24 hours from said simultaneousadministration.
 5. The method of claim 1, comprising simultaneouslyadministering 10 mg vortioxetine or a pharmaceutically acceptable saltthereof once daily through oral administration and a single dose of 10mg-20 mg vortioxetine intravenously administered with the oraladministration.
 6. The method of claim 1, wherein the firstpharmaceutical composition is in the form of a capsules, a tablet, adragee, a pill, a lozenge, a powder, or granules.
 7. The method of claim1, wherein the second pharmaceutical composition is an aqueous solution.8. A kit, comprising: an oral pharmaceutical composition comprising 5mg-20 mg vortioxetine or a pharmaceutical acceptable salt thereof foronce daily oral administration; and a second pharmaceutical compositionfor intravenous, nasal, buccal, or rectal administration comprising 5mg-40 mg vortioxetine or a pharmaceutically acceptable salt thereof. 9.The kit of claim 8, wherein the oral pharmaceutical compositioncomprises 10 mg vortioxetine or a pharmaceutical acceptable saltthereof.
 10. The kit of claim 8, wherein the oral pharmaceuticalcomposition is in the form of a capsules, a tablet, a dragee, a pill, alozenge, a powder, or granules.
 11. The kit of claim 8, wherein thesecond pharmaceutical composition is a composition for intravenousadministration.
 12. The kit of claim 8, wherein the secondpharmaceutical composition comprises 10-20 mg vortioxetine or apharmaceutically acceptable salt thereof.
 13. The kit of claim 8,wherein the second pharmaceutical composition is an aqueous solution.